In an attempt to develop sustained release delivery systems, polymeric matrices have been widely investigated as possible carriers of a variety of biologically active agents. Problems in forming viable polymeric systems for delivery of many types of agents have been difficult to overcome, however. For example, polymeric carrier matrices have often been loaded with biologically active agents by either development of a crosslinked matrix in the presence of the agent or by swelling a pre-formed, crosslinked polymer in a solution of the agent. Problems with such systems include reaction and subsequent inactivation of the unprotected agent during and following gel loading as well as problems due to solubility limitations, as many biologically active agents are only sparingly soluble in aqueous environments and thus must be loaded into a pre-existing hydrogel in a non-aqueous environment. Unfortunately, many of the biologically active agents of interest will be denatured or otherwise inactivated in such a non-aqueous environment.
Usefulness of existing matrix delivery systems in achieving slow and controlled release of loaded materials has also been limited. For instance, delivery rates of the loaded materials from existing systems have been estimated based primarily upon diffusion rates of the biologically active agents within the encapsulating matrix and/or degradation rate of the matrix itself. Due to the extreme sensitivities of solute diffusivities to various matrix and solute properties as well as system variations that can occur during matrix fabrication, poor control over delivery rates of agents from existing systems has been obtained. Problems with existing systems include initial ‘bursts’ of drugs released in large and uncontrollable quantities; non-constant or pulsatile delivery of materials from the carrier matrix; continuously decreasing release rates (first-order release profiles); unacceptably fast delivery of materials from the carrier matrix; and/or low release efficiency due to reaction of the materials with the matrix components.
Methods have been attempted to slow the release of the agents from the matrices. Development of matrix networks with smaller mesh sizes and therefore lower solute permeabilities has been examined in an attempt to slow the release rates of the agents encapsulated within the networks. The releasable solute itself has also been modified in attempts to slow its release. For example, chemical derivatization of the agents in the form of ‘prodrugs’ has been used to bind as well as to protect the agent within the matrix. Other methods have included development of a two-phase carrier matrix with the active agent sequestered within one of the phases as well as development of particular network characteristics in the carrier matrix. For example, utilization of heparin incorporation into a drug delivery matrix has been suggested in U.S. Patent Application Publication 2003/0187232 to Hubbell, et al., and U.S. Pat. No. 6,723,344 to Sakiyama-Elbert, et al., so as to non-covalently bind a drug to the heparin and slow the diffusion rate of the drug within the matrix. However, the disclosed processes often involve chemical derivatization of the drugs so as to develop the necessary heparin-binding capability in the materials. In addition, while such systems may slow drug delivery as compared to pure, diffusion-based drug delivery, they still do not provide any methods for controlling or predetermining a particular drug delivery rate. In effect, such systems provide at most an inherent drug delivery rate with little or no control options.
Other problems exist with existing systems, as well. For example, derivatization of a biologically active agent is undesirable due to the unpredictable effect of the chemical change on agent toxicity and overall pharmacokinetics of the derivatized agents. Development of two-phase networks or networks formed of polymers including very particular blocks or materials can get expensive and complicated, and these networks are often limited to utilization with quite small biologically active agents. Development of small mesh sizes in carrier matrices also presents formation difficulties. For example, compact networks display increased hydrophobicity, which can increase the immune response of an individual to the carrier.
What is needed in the art are methods and systems that can provide controlled, sustained release of a biologically active agent from a carrier matrix with a predetermined and controllable rate of release without necessity of modifying the chemical or physical nature of the deliverable agent.